Colon cancer is the third most common cancer and the third leading cause of cancer-related mortality in the United States. For many years it was believed that colorectal cancers (CRC) evolved from advanced adenomatous polyps. In recent years, however, convincing evidence has emerged that a significant proportion of CRC develops within a small subset of serrated polyps, through a mechanism that is different from those responsible for the adenoma-carcinoma developmental progression. The two most common epithelial polyp in the colorectum are adenomas and serrated polyps. Serrated polyps are morphologically characterized by a saw-toothed unfolding of the crypt epithelium. Currently, serrated polyps are grouped in 4 major categories: hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed serrated polyps. Serrated polyps have a striking subtype dependent location in the gut. Hyperplastic polyps are most frequently found in the left colon and rectum, while sessile serrated adenomas are usually found in the right colon. Historically, hyperplastic polyps have been considered to have little or no malignant potential. This view, however, has changed recently, as evidence has emerged that hyperplastic polyps display molecular features seen in neoplastic lesions, such as microsatellite instability (MSI), aberrant DNA methylation, and mutations in BRAF and KRAS genes. In addition to KRAS and BRAF mutations, our work suggests that activation of the EGFR receptor also promotes the development of serrated polyps. We have developed a novel model for serrated polyps in mice that represents a subset of human serrated polyps that arise independent of activating mutations in BRAF or KRAS, but rather occur due to increased activity of the EGFR receptor. This model presents morphological and biochemical similarities to serrated polyps in humans. Strikingly, similar to human serrated polyps, serrated polyps in HBUS mice develop in a specific location of the gut and are dependent on both genetic and environmental factors. In this proposal we will investigate how one such an environmental factor, namely the microbiota, affects the development of serrated polyps. Aim 1 is focused on the identification of the causative organism(s). Aim 2 is aimed at understanding how the microbiota affects the host and how this leads to the development of serrated polyps. A team of experts in microbiome (J. Faith, and J.C. Clemente, Sinai), microRNA biology (B. Brown, Sinai), methylome (Daniel Carvalho, Toronto) and pathology (Noam Harpaz, Sinai) will assist us in these studies.